Interleukin-8 is the single most up-regulated gene in whole genome profiling of H. pylori exposed gastric epithelial cells

Eftang, Lars Lohne; Esbensen, Ying; Tannæs, Tone; Bukholm, Ida Rashida Khan; Bukholm, Geir

doi:10.1186/1471-2180-12-9

Cited by 71 publications

(68 citation statements)

References 72 publications

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“…ASPP2 is often down-regulated in many aggressive malignancies and gastric cancers (35)(36)(37). Infection with Hp and delivery of CagA increases the level of ASPP2 (21,38). Furthermore, after Hp infection, CagA coimmunoprecipitates with ASPP2 and alters its proapoptotic function (21).…”

Section: Significancementioning

confidence: 99%

Structure of the Helicobacter pylori CagA oncoprotein bound to the human tumor suppressor ASPP2

Nešić

Buti

Lü

et al. 2014

Proc. Natl. Acad. Sci. U.S.A.

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The Cytotoxin associated gene A (CagA) protein of Helicobacter pylori is associated with increased virulence and risk of cancer. Recent proteomic studies have demonstrated an association of CagA with the human tumor suppressor Apoptosis-stimulating Protein of p53-2 (ASPP2). We present here a genetic, biochemical, and structural analysis of CagA with ASPP2. Domain delineation of the 120-kDa CagA protein revealed a stable N-terminal subdomain that was used in a yeast two-hybrid screen that identified the proline-rich domain of ASPP2 as a host cellular target. Biochemical experiments confirm this interaction. The cocrystal structure to 2.0-Å resolution of this N-terminal subdomain of CagA with a 7-kDa proline-rich sequence of ASPP2 reveals that this domain of CagA forms a highly specialized three-helix bundle, with large insertions in the loops connecting the helices. These insertions come together to form a deep binding cleft for a highly conserved 20-aa peptide of ASPP2. ASPP2 forms an extended helix in this groove of CagA, burying more than 1,000 Å 2 of surface area. This interaction is disrupted in vitro and in vivo by structure-based, loss-of-contact point mutations of key residues in either CagA or ASPP2. Disruption of CagA and ASPP2 binding alters the function of ASPP2 and leads to the decreased survival of H. pyloriinfected cells.

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Section: Significancementioning

confidence: 99%

Structure of the Helicobacter pylori CagA oncoprotein bound to the human tumor suppressor ASPP2

Nešić

Buti

Lü

et al. 2014

Proc. Natl. Acad. Sci. U.S.A.

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“…IL-8 production is also recognized as an early response to H. pylori by the gastric epithelium (14). A number of H. pylori factors are known to cause gastric inflammation and epithelial damage.…”

Section: Discussionmentioning

confidence: 99%

“…Induction of cytokine secretion by H. pylori depends on both the host genetic background and microbial virulence (9). Among these cytokines, IL-8 is the most highly expressed gene in H. pylori-infected gastric epithelial cells and appears to play a major role in the epithelial cell response to H. pylori infection and in the pathological processes leading to gastric disease (14,15). Several studies have demonstrated increased IL-8 production and secretion in response to H. pylori both in vivo and in vitro (16,17).…”

mentioning

confidence: 99%

The C-Terminal Disulfide Bonds of Helicobacter pylori GroES Are Critical for IL-8 Secretion via the TLR4-Dependent Pathway in Gastric Epithelial Cells

Yang

Lee

et al. 2015

The Journal of Immunology

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Helicobacter pylori GroES (HpGroES), a potent immunogen, is a secreted virulence factor that stimulates production of proinflammatory cytokines and may contribute to gastric carcinogenesis. HpGroES is larger than other bacterial orthologs because of an additional C-terminal region, known as domain B. We found that the HpGroES-induced IL-8 release by human gastric epithelial cells was dependent on activation of the MAPK and NF-κB pathways. HpGroES lacking domain B was unable to induce IL-8 release. Additionally, a TLR4 inhibitor significantly inhibited IL-8 secretion and reduced HpGroES-induced activation of MAPKs. Furthermore, HpGroES-induced IL-8 release by primary gastric epithelial cells from TLR4−/− mice was significantly lower than from wild-type mice. We also found that HpGroES bound to TLR4 in cell lysates and colocalized with TLR4 on the cell membrane only when domain B was present. We then constructed two deletion mutants lacking C-terminal regions and mutants with point mutations of two of the four cysteine residues, C111 and C112, in domain B and found that the deletion mutants and a double mutant lacking the C94–C111 and C95–C112 disulfide bonds were unable to interact with TLR4 or induce IL-8 release. We conclude that HpGroES, in which a unique conformational structure, domain B, is generated by these two disulfide bonds, induces IL-8 secretion via a TLR4-dependent mechanism.

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“…Accordingly, an H. pylori mutant strain lacking pldA1 is unable to colonize the murine gastric mucosa (77), and strains isolated from patients suffering peptic ulcer display high lysophospholipid content (78). However, pldA1expression does not play a role in enhancing IL-8 production or the acute inflammatory response to H. pylori (79).…”

Section: Acyl Hydrolases: Phospholipases a And Bmentioning

confidence: 99%

Bacterial Sphingomyelinases and Phospholipases as Virulence Factors

Flores-Dı́az

Monturiol-Gross

Naylor

et al. 2016

Microbiol Mol Biol Rev

165

143

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SUMMARYBacterial sphingomyelinases and phospholipases are a heterogeneous group of esterases which are usually surface associated or secreted by a wide variety of Gram-positive and Gram-negative bacteria. These enzymes hydrolyze sphingomyelin and glycerophospholipids, respectively, generating products identical to the ones produced by eukaryotic enzymes which play crucial roles in distinct physiological processes, including membrane dynamics, cellular signaling, migration, growth, and death. Several bacterial sphingomyelinases and phospholipases are essential for virulence of extracellular, facultative, or obligate intracellular pathogens, as these enzymes contribute to phagosomal escape or phagosomal maturation avoidance, favoring tissue colonization, infection establishment and progression, or immune response evasion. This work presents a classification proposal for bacterial sphingomyelinases and phospholipases that considers not only their enzymatic activities but also their structural aspects. An overview of the main physiopathological activities is provided for each enzyme type, as are examples in which inactivation of a sphingomyelinase- or a phospholipase-encoding gene impairs the virulence of a pathogen. The identification of sphingomyelinases and phospholipases important for bacterial pathogenesis and the development of inhibitors for these enzymes could generate candidate vaccines and therapeutic agents, which will diminish the impacts of the associated human and animal diseases.

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Interleukin-8 is the single most up-regulated gene in whole genome profiling of H. pylori exposed gastric epithelial cells

Cited by 71 publications

References 72 publications

Structure of the Helicobacter pylori CagA oncoprotein bound to the human tumor suppressor ASPP2

Structure of the Helicobacter pylori CagA oncoprotein bound to the human tumor suppressor ASPP2

The C-Terminal Disulfide Bonds of Helicobacter pylori GroES Are Critical for IL-8 Secretion via the TLR4-Dependent Pathway in Gastric Epithelial Cells

Bacterial Sphingomyelinases and Phospholipases as Virulence Factors

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